1. Field of the Invention
The present invention relates to a novel succinic acid salt of a biphenyl compound, in particular crystalline solid state forms of the succinic acid salt. The biphenyl compound is expected to be useful as a therapeutic agent for treating pulmonary disorders. This invention also relates to pharmaceutical compositions comprising the salt or prepared from this salt, processes and intermediates for preparing the salt and methods of using the salt to treat a pulmonary disorder.
2. State of the Art
International Patent application no PCT/US2004/004449, publication no. WO 2004/074246 A2 (Theravance Inc, South Francisco, Calif., US) discloses novel biphenyl compounds that are useful as therapeutic agents for treating pulmonary disorders, such as chronic obstructive pulmonary disease (COPD) and asthma. In particular, the compound biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester is specifically disclosed in these applications as processing both muscarinic antagonist and β2 adrenergic receptor agonist activity. The chemical structure of biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester is represented by formula I:

Therapeutic agents useful for treating pulmonary disorders are advantageously administered directly into the respiratory tract by inhalation. In this regard, several types of pharmaceutical inhalation devices have been developed for administering therapeutic agents by inhalation, including dry powder inhalers (DPI), metered-dose inhalers (MDI) and nebulizer inhalers. When preparing pharmaceutical compositions and formulations for use in such devices, it is highly desirable to have a crystalline form of the therapeutic agent that is neither hygroscopic nor deliquescent and which has a relatively high melting point (i.e. greater than about 150° C.), thereby allowing the material to be micronized without significant decomposition or loss of crystallinity.
International Patent application no PCT/US2004/004449, publication no. WO 2004/074246 A2 (Theravance Inc, South San Francisco, Calif., US), at page 135, as Example 35, describes the preparation of the compound of formula I, as the ditrifluoroacetate salt, in a lyophilised form.
International Patent application no PCT/US2005/029013, publication no. WO 2006/023454, filed 15 Aug. 2005, (Theravance Inc, South San Francisco, Calif., US) describes crystalline 1,2-ethanedisulfonic acid salts of the compound of formula I.
There remains the need to identify further stable, non-deliquescent, crystalline salt forms of the compound of formula I which have an acceptable level of hygroscopicity and a relatively high melting point.